In humans, low renal reabsorption of phosphate is the cause for several metabolic bone diseases. The most common disease in this group is X-linked hypophosphatemia, in which the renal abnormality leads to low levels of plasma phosphate that impair skeletal mineralization. Tile regulation of phosphate homeostasis by the kidney is incompletely understood. Changing dietary phosphate levels evoke a homeostatic response by the kidney leading to altered tubular reabsorption of phosphate to compensate for the dietary change. While the renal phosphate transporter (Npt-2) in the proximal tubule is known to be up-regulated by diets low in phosphate, knowledge of the transcriptional response of other renal genes to low phosphate diets is incomplete. Pilot data suggest that 92 genes are up-regulated in the kidney by low phosphate diets and participate in this response, while another 85 genes are down-regulated. During this project period, mice will be fed diets containing normal or low phosphate content. Kidneys will then be collected and analyzed. Genomic Affymetrix GeneChip microarrays will be used to detect specific genes affected by changes in dietary phosphate levels from among all known mouse genes. Kidneys from X-linked hypophosphatemic (Hyp) mice fed normal or low phosphate diet will also be studied. Pilot data suggest that this mutation reduces, but does not eliminate, the genomic response to low phosphate diet. Additional pilot data suggest that there are genes affected by the Hyp mutation which are unaffected by low phosphate diet. This may indicate that the gene mutated in X-linked hypophosphatemia has roles outside of mineral homeostasis. Replication will be done to establish statistically significant responses by specific genes expressed in the kidney. This project will define the genomic response of the kidney to a change in dietary phosphate levels. The affected genes will be assembled into functional metabolic pathways. This project may find novel regulatory pathways within the kidney that affect phosphate homeostasis. Whether this renal adaptation is blocked by the Hyp mutation will also be determined. The results may suggest novel therapeutic intervention that will correct phosphate transport in patients with abnormal renal function. Such intervention may improve the skeletal symptoms of patients with [unreadable] hypophosphatemic bone disease and improve their quality of life. [unreadable] [unreadable]